Flashcards
Lecture 2 Week 1 Pathophysiology
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- 1PathologyCell or tissue in normal state is able to revert to responses to stimuli or insult
Cell is unable to revert responses leads to a pathological state
Pathology - study of structural, biochemical and functional changes in cells, tissues and organs that underlie disease - 2General PathologyGeneral pathology - common reactions of tissues and organs to injurious stimuli e.g. inflammatory response to bacterial infection is similar in most tissues
- 3Systemic PathologyDeals with organ specific diseases
e.g. heart disease and kidney disease - 4Pathological processCause or aetiology
Pathogenesis
Morphological changes
Clinical manifestation - 5Cause or aetiologyCan be external or internal
External (acquired) - macro and micro environment e.g. radiation, infectious, nutrition
Internal (inherited) - genetic e.g. mutations and chromosomal abnormalities
Combination of multiple causes lead to disease E.g. diabetes is a multifactorial disease involving genetic factors and dietary and lifestyle factors - 6PathogenesisCauses lead to a sequence of molecular, biochemical and cellular changes
Understanding of this process is important for developing therapeutic interventions and molecular diagnosis - 7Morphological changesPathogenic changes leads to changes at the tissue, organ or individual level
Characteristic of a disease or aetiology and thus used for diagnosis
Histological (cellular) changes can be visualised microscopically, biochemical changes by diagnostic testing of body fluids (blood, urine) and systemic changes by various scanning methods - 8Clinical manifestationPathogenic and structural changes leads to functional abnormalities that lead to clinical symptoms of a disease and its progression E.g. breathlessness in heart disease, joint pain/stiffness in arthritis
- 9Cellular responses to srtessHomeostasis
Adaptation
Injury
Death - 10HomeostasisNormal state of cell. Normal cell is able to meet physiological demands e.g. demands of daily activities
- 11AdaptationMeet a continuous physiological demand, the cell can adapt to an altered steady state.
State is reversible when the demand is removed and cell recovers to its normal state without harmful consequences. Adaptation is a normal cellular response
E.g. physical changes during pregnancy, muscular changes from exercise - 12InjuryWhen cell is unable to adapt to continuous physiological challenge or is exposed to a stress stimulus that leads to cell injury. Cell injury is reversible up to a certain point (if challenge/stress is removed) but irreversible beyond a point
- 13DeathIrreversible cell injury leads to cell death. Cell death is not always an abnormal process. Normal essential process during embryogenesis and organ development and for tissue homeostasis
E.g. skin cells between digits die for hand formation - 14Mechanisms of adaptationHypertrophy
Hyperplasia
Cellular adaptation to physiological demands can take various different forms and is cell type dependent - 15HypertrophyIncrease in cell size to increase metabolic activity of the tissue/organ in response to mechanical demand or hormonal and growth factors. It occurs in non-dividing cells and results from increased protein synthesis and assembly of additional intracellular structural components
E.g. enlargement of skeletal muscle fibers in body builders, enlargement of uterus during pregnancy, enlargement of heart muscles to increase strength to pump blood - 16HyperplasiaIncrease in cell number to increase functional capacity of tissue, organ in response to hormones and growth factors or to compensate for tissue damage/resection. Only occur in dividing cells
E.g. proliferation of bone marrow cells to replace blood cells after and acute bleed, regeneration of liver lobe after donation of a lobe for transplantation
Hypertrophy and hyperplasia often coexist to meet physiological demand by increasing cell size and cell number. E.g. proliferation and enlargement of glandular epithelium in female brest at puberty and during pregnancy - 17Mechanisms of adaptationAtrophy
Metaplasia - 18AtrophyDecrease in cell size and number and leads to reduction in size of tissue/organ in response to neighbouring cues or loss of hormone stimulation. results from decrease in protein synthesis and increase in protein degradation and cell death
E.g. degeneration of notochord during development (irreversible atrophy); reduction in size of uterus after childbirth; reduction in skeletal muscle in a fractured limb immbolised in a cast - 19MetaplasiaOne cell type is replaced by another cell type that has better adaptability to stress stimulus. It results from reprogramming of stem cells or undifferentiated cells present in tissue and not from change in cell morphology, in response to growth factors and cytokine signalling
E.g. replacement of columar by squamous epithelium in respiratory tract due to chronic irritation and in regular cigarette smokers; replacement of squamous by columnar epithelium due to stones in salivary or bile ducts - 20AdaptationPhysiological process but it can also occur in pathological conditions due to changes in micro environment of tissue/organ
Physiological adaptation beyond a certain point can lead to a pathological state - 21Pathologic adaptationPathologic hypertrophy
Pathologic hyperplasia
Pathologic atrophy
Pathologic Metaplasia - 22Pathologic hypertrophyEnlargement of heart muscles beyond the point of adaptation - arrhythmias or heart failure and death
- 23Pathologic hyperplasiaEstrogen and progesterone imbalance - endometrial hyperplasia - excessive menstrual bleeding (reversible if hormonal balance is restored
Endometrial hyperplasia - increase in risk of endometrial cancer (irreversible) - 24Pathologic atrophyMuscle disuse - loss of muscle mass (reversible)
Loss of innervation - loss of muscle fibres - paralysis (irreversible)
Reduced blood supply to heart or brain due to arterial occlusion - nutrient and oxygen deprivation - heart disease or stroke (irreversible) - 25Pathologic MetaplasiaColumnar to squamous epithelium metaplasia in respiratory tract - squamous cell carcinoma
Squamous to columnar epithelium metaplasia in esophagus due to gastric acid reflux - Barrett oesophagus - esophageal cancer - 26Cell injury - causesPhysical agents
Chemical agents
Infectious agents
Immunological reactions
Nutritional imbalance
Genetic defects
Oxygen deprivation - 27Physical agentsTrauma from accident, heat/frost burns from extreme temperatures, radiation exposure, electric shock, changes in atmospheric pressure
- 28Chemical agentsPoisons, air or food pollutants (pesticides, insectides), alcohol, smoking and recreational drugs, therapeutic drugs (side effects), imbalance in salt/sugar concentrations (osmotic imbalance), high oxygen concentration
- 29Infectious agentsViruses, bacteria, fungi, parasites, worms etc
- 30Immunological reactionsTo self antigens in autoimmune diseases, to infectious agents and enviornmental substances
- 31Nutritional imbalanceMalnutrition, anorexia nervosa, over nutrition, vitamin deficiencies, iron deficiency
- 32Genetic defectsDisorders caused by single gene mutations (in born errors of metabolism sickle cell anaemia) or chromosomal abnormalities
- 33Oxygen deprivationReduced blood supply (ischaemia), insufficient blood oxygenation due to heart or respiratory problems, decreased oxygen carrying capacity of blood due to anaemia or CO poisoning
- 34Factors that influence cell injuryCellular response to an injurious stimulus depends upon dose, duration and nature of stimulus
E.g. small dose of noxious chemical may induce reversible injury whereas large dose of same chemical may lead to irreversible cell injury or cell death. Short exposure to ultraviolet radiation from sunlight may cause a reversible skin rash whereas prolonged exposure may lead to severe sunburn
Individual responses to same stimulus are variable. This can be due to variability in genetic make up
E.g. consumption of equal amounts of alcohol by two individuals has different effects on them likely because of difference in metabolizing enzyme
Response to injury depends upon cellular environment including nutrients, hormone status and metabolic needs
E.g. muscles in leg are more resistant to loss of blood supply than heart muscles - 35Mechanisms of cell inuryDepletion of energy (ATP)
Influx calcium and loss of calcium homeostasis
Reactive oxygen species (ROS) production and oxidative stress
Mitochondrial damage
Defects in membrane permeabilitiy
DNA and protein damage
Mechanisms of cell injury are inter-connected - 36Depletion of ATPDepletion of ATP is a major cause of cell injury and necrotic cell death
Energy metabolism is altered from aerobic to anaerobic i.e. oxidative phosphorylation to glycolysis
Membrane transport is impaired due to Na+/K+ ATPase pump and Ca2+ channel failure
Protein synthesis is reduced
Endoplasmic reticulum (ER) and cell swelling
Irreversible damage to mitochondrial and lysosomal membrane leads to cell death by necrosis - 37Influx of calcium and loss of calcium homeostasisIntracellular levels of Ca2+ are lower than extracellular levels
Intracellular Ca2+ is retained in the mitochondria and ER
Release of Ca2+ from the intracelullar stores or influx through the plasma membrane leads to increased intracellular Ca2+ levels
High intracellular Ca2+ is required for muscle contraction, hormone secretion from endocrine glands and neurotransmission
Toxins or ischaemia can also lead to high intracellular Ca2+ levels that cause cell injury - 38Consequences of InfluxActivation of various degradation enzymes
plasma membrane damage
Degradation of cytoskeletal proteins
Nuclear damage and DNA fragmentation
Mitochondrial membrane permeability, activation of caspases and induction of cell death by apoptosis - 39ROS production and oxidative stressROS are mainly oxygen-derived free radicals that are chemically reactive
ROS play a role in normal cellular processes such as cell proliferation and differentiation
Balance between free radicals and antioxidants is important for normal cell function
Increased production of ROS or decreased antioxidant levels lead to oxidative stress
Oxidative stress is the major cause of cell damage in many diseases
Electron transport chain in the mitochondria is the major source of ROS in Cell
Plasma membrane enzymes NADPH oxidases also produces ROS
Mtiochondrial damage, metabolism of drugs and chemicals and pathogens are other sources of ROS in cell - 40Mitochondrial damageMitochondria play a central role in cell injury and cell death induced through various pathways
Toxins, hypoxia, increased intracellular Ca2+ and ROS levels and mutations in mitochondrial DNA can lead to mitochondrial damage - 41Consequence of mitochondrial damageFormation of mitochondrial permeability transition pore, a high conductance channel in mitochondrial membrane and loss of membrane potential. This leads to failure of oxidative phosphorylation and ATP depletion
Abnormal oxidative phosphorylation leads to increase ROS production
Release of cytochrome C and caspases from mitochondrial inter-membrane space which leads to cell death by apoptosis - 42Defects in membrane permeabilityMembrane integrity is important for cellular homeostasis and function
Physical and chemical agents, viruses and bacterial toxins, hypoxia and increased intracellular Ca2+ and ROS levels can lead to membrane permeability - 43Consequences of defects in membrane permeabilityPlasma membrane damage
Mitochondrial membrane damage
Lysosomal membrane damage that leads to leakage of degrading enzymes (DNAses, RNAses, proteases, phosphatases, glucosidases) into cytoplasm, degradation of macromolcules (DNA, RNA, proteins, glycogen) and cell death by necrosis - 44DNA and protein damageCells have mechanisms for repairing damage to DNA but if the damage is too severe and cannot be corrected, the cell initiates cell death pathways that results in cell death by apoptosis
Causes of DNA damage - radiation, DNA damaging drugs, ROS
Similarly cells have mechanisms for clearing unfolded or mis folded proteins but if such protein species accumulate and aggregate within the cell, the cell initiates the cell death pathways
Causes of protein damage - genetic mutations and ROS - 45Mechanisms of cell deathCell death can be classified into two categories
Accidental - sudden death due to severe insults e.g. poisons, burns. It is not amenable to intervention
Regulated - programmed by molecular machineries int the cell and can be modulated by pharmacological or genetic interventions - 46NecrosisEnergy independent mechanism of cell death
Process of necrosis
- swelling of the cell
- plasma membrane becomes permeable
- cellular contents leak into interstitial tissue that causes inflammation
- necrotic cell debris is digested by the immune cells
- cell debris can be engulfed (myocardial infact) or liquefied (pus) by immune cells
Necrosis occurs in pathological conditions such as ischaemia-heart attack, stroke, kidney failure, neurodegenerative diseases and infections
Marker of necrosis - chromatin protein high mobility group B1 - 47ApoptosisCell death by apoptosis occurs as a normal physiological process and pathological conditions
Apoptosis is an energy dependent mechanism of cell death
Mitochondria, anti and pro apoptotic proteins and caspases play central role in apoptosis
Physiological apoptosis
- notochord regression during embryogenesis
- deletion of inter-digitial tissue for hand formation
- formation of body cavities
- removal of immeun cells after an immune response
- maintaining homeostatic cell numbers in population of cells
Examples of pathological apoptosis
- UV radiation or chemically induced DNA damage
- Neurodegenerative diseases
- Neurotrophin deprivation
Defective apoptosis and increased cell survival can lead to cancer - 48Differences between necrosis and apoptosisCell shrinkage chromatin condensation
Nucleus and DNA fragmentation
Apoptotic bodies are formed by plasma membrane blebbing
Apoptotic bodies are engulfed by immune cells without inflammation
DNA fragmentation is a marker of apoptotic cell death although DNA also fragments during necrosis - 49Intrinsic pathway of apoptosisIn a viable cell, anti-apoptotic proteins and pro apoptotic proteins are bound to each other in the outer mitochondrial membrane that prevents leakage of Cytochrome C from mitochondrial intermembrane space into the cytoplasm
Injured cell, DNA damage rearrangement of cytoskeleton or loss of survival signals activates various regulatory proteins that disrupts the binding proteins. Bax/Bak proteins oligomerize and from activate channels that release Cytochrome C into cytoplasm --> activates caspaces and in turn caspase-3 results in cell apoptosis - 50Extrinsic pathway of apoptosisDeath receptor (Fas or TNF receptor) in the plasma membrane binds to its ligand (FasL or TNF alpha) on neighbouring cell that leads to recruitment of adaptor proteins and activation of caspase-8 and -10
Activates caspase-3 that results in cell apoptosis
Extrinsic pathway of apoptosis is important in immune cells
Intrinsic and extrinsic pathways are interconnected and can occur in a cell
Caspase-3 is a reliable marker of apoptosis - 51Perforin/Granzyme pathway of apoptosisCytotoxic T cells recognise foreign antigens on host cells and secrete perforin in the plasma membrane
perforin forms pores in the plasma membrane and allows entry of granzymes (proteases) in the cells
Granzymes activates caspases including caspase 3 that leads to cell apoptosis - 52NecroptosisNecroptosis is in between necrosis and apoptosis and shares aspects of both the mechanisms
Similar to necrosis - cell and organelle swelling, plasma membrane rupture and release of contents in the neghbouring environment occurs
Similar to apoptosis - initiated by signalling through binding of plasma receptors such as TNFR1 and Fas to their respective ligands
Does not involve activation of caspases
Necroptosis can occur in physiological and pathological conditions
Necrosis, necropotsis and apoptosis form a continum - 53AutophagyProcess by which cell eats its own contents (similar to cannibalism) to recycle metabolities and clear cellular debris for maintaining cellular integrity under adverse conditions
Energy dependent process
Various types of stresses initiate autophagy as a mechanism of cell defence that leads to various beneficial effects
Autophage is prominent in atrophic cells for preserving energy
Autophagy can trigger cell death if it is unable to cope with the stress imposed on the cell
Autophage occurs in several diseases such as neurodegenerative diseases, infections and inflammatory diseases, heart disease, diabetes and cancer - 54Mechanisms of autophagyMacroautophagy is the major form of autophagy
Complex of 4 proteins induces autophagy at a site that triggers assmebly of an initiation complex and in turn to formation of an isolation membrane or phagophore
Phagophore elongates around cytosolic cargo and closes to form autophagosome. Involves coordinated action of several ubiquitin-like proteins and ubiquitin-like conjugation enzymes including LC3 that is the marker of autophagy
Autophagosome fuses with late endosomes and lysosomes to form an autophagolysosome
Lysosome enzymes degrade the inner membrane and cytosolic cargo - 55Inter-relatedness of cell death mechanismsNecrosis-apoptosis continum - Low availability of caspases and ATP can switch apoptosis to necrosis. Whether a cell undergoes necrosis or apoptosis, depends upon the extent and duration of the stress stimulus. Apoptosis and autophagy can occur separately, sequentially or simulataneously
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- PATHOPHYSIOLOGY MMED3937 FlashCards sobre Lecture 2 Week 1 Pathophysiology, criado por Paras Chrysostomou em 06-03-2017.
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